Prostate cancer has become and remains the second leading cause of cancer-related death in American men. Effective management of prostate cancer requires early detection and the availability of accurate diagnostic modalities for predicting and monitoring the disease. Increased androgen receptor (AR) expression in primary tumors of prostate cancer is a strong indicator of the disease; however, due to heterogeneity of the tumors, biopsy samples alone may not be sufficient for disease detection. Molecular imaging agents that can noninvasively provide prognostic information for distinguishing AR-positive tumors are critically important for the treatment of prostate cancer. Over the years, a number of fluorinated androgen derivatives have been synthesized and evaluated for AR binding and tissue distribution in vivo using positron emission tomography (PET). Several promising candidates have been successfully labeled with the positron emitting radionuclide fluorine-18 in efforts to develop PET tracers for tumor localization in patients with metastatic prostate cancer. For example, 16β-18F-fluoro-5α-dihydrotestosterone (18F-FDHT), a fluorinated analog of the native AR-binding ligand dihydrotestosterone, has been studied in both rat and primate models and has proven to be one of the most effective in vivo AR-binding radiotracers studied to date.
Significant interest in evaluating and monitoring AR expression in prostate cancer patients has led to multiple clinical studies using 18F-FDHT. The overall goal of these studies was to assess the potential of 18F-FDHT as a diagnostic tool for imaging AR expression in prostate cancer patients. In these studies, 18F-FDHT was found to bind AR in both primary tumor and metastatic sites suggesting its crucial role in prostate cancer imaging. Clinical efficacy proved promising, even when compared to 18F-FDG in patients with castrate-resistant prostate cancer. More recently, a study by Beattie et al. evaluated the pharmacokinetic properties of 18F-FDHT and found that uptake of the tracer in prostate tumors correlated reasonably well with AR expression in metastatic prostate cancer. Beattie et al., Pharmacokinetic Assessment of the Uptake of 16β-18F-Fluoro-5α-Dihydrotestosterone (FDHT) in Prostate Tumors as Measured by PET. J. Nucl. Med. 51, 183-192 (2010). As more clinical studies are conducted, the potential of 18F-FDHT to elucidate the role of AR expression in metastatic prostate cancer becomes clearer and may lead to improved therapeutic approaches and clinical management of the disease.
The manual synthesis of 18F-FDHT was reported by Liu et al. (1992b) via the precursor (precursor 1) 16α-[[(trifluoromethyl)sulfonyl]oxy]-3,3-(ethylenedioxy)androstan-17-one (as illustrated in FIG. 1). Nucleophilic displacement of the triflate of precursor 1 with nBu4N18F gave the fluorinated intermediate 2, which underwent subsequent reduction via lithium aluminum hydride (LiAlH4) to afford the α-hydroxyl intermediate 3. Acid-catalyzed deprotection of the ketal yielded the desired compound, 18F-FDHT, in three total steps. The total synthesis time for the manual process, including high-performance liquid chromatography (HPLC) purification, was 90 min. The reported decay-corrected radiochemical yield (RCY) was 31%-48%, and the specific activity was 1.2 Ci/μmol (43 GBq/μmol).
The demand for 18F-FDHT is expected to increase as the clinical potential of this PET tracer to predict AR expression levels in prostate cancer patients is being recognized. Currently, the clinical production of 18F-FDHT is generally performed manually by trained radiochemists; as such, its widespread use is limited to a few sites. Due to the highly reactive nature of LiAlH4 the highly exothermic reduction step in the manual synthesis process is performed at −78° C. to tame the reactivity of the reducing reagent and also to minimize the formation of unwanted side products. Automation of this synthesis would enable many more facilities currently equipped for PET synthesis to routinely obtain 18F-FDHT without the need for specialized personnel. Automated radiosynthesizers, however, do not include the ability to perform reduction reactions at such low temperatures.